Peripheral inflammatory biomarkers define biotypes of bipolar depression.

We identified biologically relevant moderators of response to tumor necrosis factor (TNF)-α inhibitor, infliximab, among 60 individuals with bipolar depression. Data were derived from a 12-week, randomized, placebo-controlled clinical trial secondarily evaluating the efficacy of infliximab on a measure of anhedonia (i.e., Snaith-Hamilton Pleasure Scale). Three inflammatory biotypes were derived from peripheral cytokine measurements using an iterative, machine learning-based approach. Infliximab-randomized participants classified as biotype 3 exhibited lower baseline concentrations of pro- and anti-inflammatory cytokines and soluble TNF receptor-1 and reported greater pro-hedonic improvements, relative to those classified as biotype 1 or 2. Pretreatment biotypes also moderated changes in neuroinflammatory substrates relevant to infliximab's hypothesized mechanism of action. Neuronal origin-enriched extracellular vesicle (NEV) protein concentrations were reduced to two factors using principal axis factoring: phosphorylated nuclear factorκB (p-NFκB), Fas-associated death domain (p-FADD), and IκB kinase (p-IKKα/ß) and TNF receptor-1 (TNFR1) comprised factor "NEV1," whereas phosphorylated insulin receptor substrate-1 (p-IRS1), p38 mitogen-activated protein kinase (p-p38), and c-Jun N-terminal kinase (p-JNK) constituted "NEV2". Among infliximab-randomized subjects classified as biotype 3, NEV1 scores were decreased at weeks 2 and 6 and increased at week 12, relative to baseline, and NEV2 scores increased over time. Decreases in NEV1 scores and increases in NEV2 scores were associated with greater reductions in anhedonic symptoms in our classification and regression tree model (r2 = 0.22, RMSE = 0.08). Our findings provide preliminary evidence supporting the hypothesis that the pro-hedonic effects of infliximab require modulation of multiple TNF-α signaling pathways, including NF-κB, IRS1, and MAPK.

A prospective study of social competence in survivors of pediatric brain and solid tumors.

BACKGROUND/OBJECTIVES: Survivors of pediatric brain tumors are at increased risk for difficulties with social competence, including poor social information processing (SIP) and peer relationships. Improved survival rates heighten the need to better understand these challenges and if they are specific to survivors of pediatric brain tumors versus survivors of other childhood cancers. METHODS: Fifty-one survivors of pediatric brain tumors and 34 survivors of pediatric solid tumors completed evaluations of SIP and peer relationship quality within six months of completing treatment and one year later. Caregivers completed a measure of social skills. Linear mixed models evaluated differences between survivors of pediatric brain and solid tumors on SIP and social skills and how indices of SIP were associated with peer relationships over time. RESULTS: The two groups did not differ on indices of SIP or social skills over time. A three-way interaction between measures of SIP, group, and time predicted peer relationships. Survivors of pediatric solid tumors showed a positive association between baseline social skills and theory of mind and peer relationships over time, whereas survivors of pediatric brain tumors showed an inverse association between baseline social skills and theory of mind and peer relationships over time. CONCLUSION: Findings revealed unanticipated associations between baseline SIP and social skills and peer relationships over time among survivors of pediatric brain tumors. Additional research is needed to elucidate the factors most influential on peer relationships in this group to inform interventions.

Efficacy of adjunctive infliximab vs. placebo in the treatment of anhedonia in bipolar I/II depression.

We investigated the efficacy of tumour necrosis factor (TNF)-α antagonist infliximab on a measure of anhedonia amongst individuals with bipolar I/II depression (ClinicalTrials.gov identifier NCT02363738). Adults (ages 18-65) with bipolar I/II disorder currently experiencing a major depressive episode with a higher probability of inflammatory activity (i.e., meeting one or more of the following inflammatory/metabolic criteria: obesity and dyslipidemia/hypertension, daily cigarette smoking, diabetes mellitus, migraine, inflammatory bowel disease, and/or C-reactive protein level of ⩾5 mg/L) were enrolled in a double-blind, 12-week clinical trial of adjunctive infliximab (5 mg/kg) and saline control, which were administered at weeks 0, 2, and 6. The primary outcome measure for the present secondary analysis was change in the Snaith-Hamilton Pleasure Scale (SHAPS) total score between placebo- and infliximab-treated subjects from baseline to weeks 6 and 12. Plasma concentrations of TNF-α and soluble TNF receptors (sTNFR) 1 and 2 were assessed at weeks 0, 2, 6, and 12. Sixty eligible adults received treatment with infliximab (n=29) or placebo (n=31); 47 subjects completed the study (infliximab: n=21, placebo: n=26). Overall, infliximab-randomized subjects exhibited significantly larger increases in SHAPS total score, denoting greater reductions in anhedonic symptoms, when compared to placebo-randomized subjects (treatment × time interaction effect: χ2=7.15,df=2,p=0.03). Anti-anhedonic efficacy was moderated by baseline plasma levels of TNF-α and sTNFR1, but not by changes in TNF-α or sTNFR1 concentrations. Baseline and changes in sTNFR2 concentrations did not moderate anti-anhedonic efficacy. Infliximab significantly improved a measure of anhedonia relative to placebo in adults with bipolar I/II depression at week 6; intervention efficacy was not sustained 6 weeks after the final infusion.

A randomized controlled trial of MoodSwings 2.0: An internet-based self-management program for bipolar disorder.

OBJECTIVES: MoodSwings 2.0 is an online self-guided intervention for bipolar disorder that includes educational modules, interactive tools, and discussion forums. The primary aim of the study was to determine if participation in MoodSwings 2.0 would result in decreased symptoms of depression and mania compared to the control condition. Secondary aims were to identify improvements in core depression symptoms, quality of life, medication adherence, functioning, and time to relapse. METHODS: This was a three-arm randomized controlled trial that compared two intervention arms against a peer support control group (forum). A total of 304 adults aged 21 to 65 years with a diagnosis of bipolar disorder were assigned to a forum-only control group (Group 1; n = 102), a forum plus modules treatment group (Group 2; n = 102), or a forum, modules, and tools treatment group (Group 3; n = 100), in addition to usual care. RESULTS: There was a significant intervention impact showing improvement on the primary outcome of depression for Group 2 compared to Group 1 (P = .05) with effect sizes (Cohen's d) ranging from 0.17 to 0.43. There was also a significant intervention impact showing improvement on the secondary outcome of core depression for Group 2 (P = .02) and Group 3 (P = .05), but worse physical functioning for Group 3 (P = .01), compared to Group 1. CONCLUSIONS: This study provides evidence of the efficacy of internet-based psychoeducation interventions for bipolar disorder in reducing depressive symptoms. Further investigation is needed to assess effectiveness in a public program.

Evaluating discussion board engagement in the MoodSwings online self-help program for bipolar disorder: protocol for an observational prospective cohort study.

BACKGROUND: Online, self-guided programs exist for a wide range of mental health conditions, including bipolar disorder, and discussion boards are often part of these interventions. The impact engagement with these discussion boards has on the psychosocial well-being of users is largely unknown. More specifically we need to clarify the influence of the type and level of engagement on outcomes. The primary aim of this exploratory study is to determine if there is a relationship between different types (active, passive or none) and levels (high, mid and low) of discussion board engagement and improvement in outcome measures from baseline to follow up, with a focus on self-reported social support, stigma, quality of life and levels of depression and mania. The secondary aim of this study is to identify any differences in demographic variables among discussion users. METHODS/DESIGN: The present study is a sub-study of the MoodSwings 2.0 3-arm randomised controlled trial (discussion board only (arm 1), discussion board plus psychoeducation (arm 2), discussion board, psychoeducation plus cognitive behavioural therapy-based tools (arm 3)). Discussion engagement will be measured via online participant activity monitoring. Assessments include online self-report as well as blinded phone interviews at baseline, 3, 6, 9 and 12 months follow up. DISCUSSION: The results of this study will help to inform future programs about whether or not discussion boards are a beneficial inclusion in online self-help interventions. It will also help to determine if motivating users to actively engage in online discussion is necessary, and if so, what level of engagement is optimal to produce the most benefit. Future programs may benefit through being able to identify those most likely to poorly engage, based on demographic variables, so motivational strategies can be targeted accordingly. TRIAL REGISTRATION: ClinicalTrials.gov NCT02118623 registered April 15 2014 and NCT02106078 registered May 16 2013.

Fluctuating hypermetropia due to intraocular lens displacement caused by iris pigment epithelial cyst.

Purpose: To report a case of hyperopic shift following lens replacement surgery due to an enlarging iris pigment epithelial (IPE) cyst. Observations: A gentleman presented with reduced visual acuity (Snellen unaided 20/25) 12 months followed lens replacement surgery. Examination revealed a retro-pupillary iris lesion that appeared to be displacing the posterior chamber intraocular lens (IOL) and was causing a hyperopic shift (refraction +2.00). Anterior segment optical coherence tomography imaging confirmed this to be an IPE cyst with a posteriorly displaced IOL body. After observation over 30 months, the IPE cyst spontaneously reduced in size and the IOL returned to a more physiological position. Unaided visual acuity improved to Snellen 20/16 and refraction improved to +0.50. Conclusions and Importance: To our knowledge, an IPE cyst that shows growth following intraocular surgery has not previously been reported. This growth resulted in a hyperopic shift due to posterior displacement of the IOL. This case demonstrates spontaneous regression of the cyst, and suggests that over time these cysts can change in size.

Informing DSM-5: biological boundaries between bipolar I disorder, schizoaffective disorder, and schizophrenia.

BACKGROUND: The fifth version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) opted to retain existing diagnostic boundaries between bipolar I disorder, schizoaffective disorder, and schizophrenia. The debate preceding this decision focused on understanding the biologic basis of these major mental illnesses. Evidence from genetics, neuroscience, and pharmacotherapeutics informed the DSM-5 development process. The following discussion will emphasize some of the key factors at the forefront of the debate. DISCUSSION: Family studies suggest a clear genetic link between bipolar I disorder, schizoaffective disorder, and schizophrenia. However, large-scale genome-wide association studies have not been successful in identifying susceptibility genes that make substantial etiological contributions. Boundaries between psychotic disorders are not further clarified by looking at brain morphology. The fact that symptoms of bipolar I disorder, but not schizophrenia, are often responsive to medications such as lithium and other anticonvulsants must be interpreted within a larger framework of biological research. SUMMARY: For DSM-5, existing nosological boundaries between bipolar I disorder and schizophrenia were retained and schizoaffective disorder preserved as an independent diagnosis since the biological data are not yet compelling enough to justify a move to a more neurodevelopmentally continuous model of psychosis.

All in the Family: How Parental Criticism Impacts Depressive Symptoms in Youth.

Despite a strong connection between family environment and mood symptoms in youth, little research to date has examined potential underlying mechanisms. We propose an etiological model investigating how parenting (i.e., expressed emotion, or EE) affects youth depression by shaping their emotion regulation abilities. Forty-six youth and caregivers participated in this cross-sectional study. Family environment was assessed using the Five-Minute Speech Sample (FMSS) and the Levels of Expressed Emotion Scale (LEE). The Difficulties in Emotion Regulation Scale (DERS) and the Children's Depression Rating Scale-Revised (CDRS-R) were used to assess youth emotion regulation and depressive symptoms, respectively. Analyses demonstrated no significant relationships between type of reporter (i.e., independent rater, parent, youth) of parental EE and criticism. Mediation analyses suggested that youth-reported parental EE predicted greater levels of youth depressive symptoms, and that this association was mediated by emotion regulation. This study has direct clinical implications, elucidating the importance of strengthening positive parent-child communication to support the development of emotion regulation skills and psychological well-being for youth.

A pilot trial of quetiapine, lithium, or placebo added to divalproex sodium for hypomanic or manic episodes in ambulatory adults with bipolar I disorder.

BACKGROUND: Many patients with bipolar I disorder do not respond to monotherapy treatment with mood-stabilizing medications, and combination regimens are commonly used in both inpatient and outpatient settings for the acute and maintenance treatment of bipolar disorder. We studied whether combination therapy is more effective than monotherapy for the acute treatment of subjects with bipolar I disorder currently experiencing manic symptoms. The primary hypothesis was that combination treatments would be associated with greater reductions in symptoms of mania and hypomania than monotherapy alone. The secondary hypothesis was that combination therapies would be associated with lower depression levels than monotherapy alone. Last, a post-hoc exploratory aim was used to examine whether the effect of side effect severity on risk-of-dropout would be greater in combination therapies than in monotherapy alone. RESULTS: In this 12-week, double-blind, placebo-controlled ambulatory pilot trial, participants (n = 75) with bipolar I disorder were randomly assigned to: (1) monotherapy divalproex plus placebo (DVP + PBO), (2) combination therapy of divalproex plus blinded lithium (DVP + Li) or (3) divalproex plus blinded quetiapine (DVP + QTP). Combination therapies (vs. monotherapy) were not associated with improved symptoms of mania, hypomania or depression. The effect of side effect severity on study retention did not differ between combination therapies and monotherapy. However, the risk-of-dropout was significantly greater in the DVP + Li arm versus the DVP + PBO arm. CONCLUSIONS: No longitudinal differences in mania, hypomania or depression were found between combination therapies and monotherapy. The effect of side effect severity on study retention did not differ between groups. Due to the small sample size and differential rates of attrition between treatment arms, results of this pilot trial must be interpreted with caution. Trial registration ClinicalTrials.gov identifier: NCT00183443.

Aberrant Neural Response to Social Exclusion Without Significantly Greater Distress in Youth With Bipolar Disorder: Preliminary Findings.

Background: Little is known about the effects of social exclusion on youth with bipolar disorder (BD). Understanding these effects and the functional neural correlates of social exclusion in youth with BD may establish differences from healthy youth and help identify areas of intervention. Methods: We investigated brain function in 19 youth with BD and 14 age and gender matched healthy control (HC) participants while performing Cyberball, an fMRI social exclusion task. Whole brain activation, region-of-interest, and functional connectivity were compared between groups and examined with behavioral measures. Results: Compared with the HC group, youth with BD exhibited greater activation in the left fusiform gyrus (FFG) during social exclusion. Functional connectivity between the left FFG and the posterior cingulate/precuneus was significantly greater in the HC compared with the BD group. For the HC group only, age and subjective distress during Cyberball significantly predicted mean FFG activation. No significant differences in distress during social exclusion were found between groups. Conclusion: Although preliminary due to small sample size, these data suggest that youth with BD process social exclusion in a manner that focuses on basic visual information while healthy youth make use of past experiences to interpret current social encounters. This difference may account for the social cognitive issues experienced by youth with BD, which can lead to more severe anxiety and mood symptoms.

Family support and depressive symptoms: a 23-year follow-up.

We examined change in family support and depressive symptoms over the course of 23 years and included the potential moderators of gender and participation in treatment. A sample of 373 depressed individuals provided data in five waves, with baseline, 1-year, 4-year, 10-year, and 23-year follow-ups. Multilevel modeling was used to evaluate longitudinal relationships between variables. Higher family support was associated with less depression at baseline and predicted a steeper trajectory of recovery from depression over 23 years. This relationship was moderated by gender, such that women with supportive families reported the most rapid recovery from depression. Evaluating family context may be clinically relevant when beginning treatment with a depressed patient, particularly for female patients.

Effects of infliximab on brain neurochemistry of adults with bipolar depression.

OBJECTIVES: To explore the relationship between inflammation and neuronal metabolism in bipolar disorder (BD) by evaluating the neurochemical effects of the tumor necrosis factor-α (TNF-α) antagonist infliximab among individuals with bipolar depression METHODS: This is a post-hoc, exploratory analysis from a 12-week, randomized, double-blind, placebo-controlled trial with infliximab for adults with bipolar depression. We assessed the effects of infliximab on concentration of metabolites in the prefrontal cortex, using proton-magnetic resonance spectroscopy (1H-MRS), as well as its association with clinical outcomes (i.e. depressive symptom severity and cognitive function). RESULTS: Eighteen participants in the placebo and 15 in the infliximab group were included in this analysis. In the pre-specified primary outcome, there were no significant effects of treatment on prefrontal concentrations of N-acetylaspartate (NAA; p = 0.712). In the secondary analyses, there was a significant treatment by time interaction for glutamate (Glx; p = 0.018), indicating that Glx levels decreased in infliximab-treated patients, relative to placebo. Treatment group significantly moderated the association between changes in Glx levels and changes in a neurocognitive test (i.e. Digit Symbol Substitution Test; p = 0.014), indicating that in infliximab-treated participants reductions in Glx were associated with cognitive improvement. CONCLUSIONS: Treatment with infliximab did not affect prefrontal NAA concentration in adults with BD. Exploratory analysis suggested a potential effect of treatment on the glutamate system, a finding that should be confirmed and validated by additional studies.

Exploring brain insulin resistance in adults with bipolar depression using extracellular vesicles of neuronal origin.

Accumulating evidence suggests that disrupted insulin signaling is involved in bipolar disorder (BD) pathogenesis. Herein, we aimed to directly explore the potential role of neuronal insulin signaling using an innovative technique based on biomarkers derived from plasma extracellular vesicles enriched for neuronal origin (NEVs). We leveraged plasma samples from a randomized, double-blind, placebo-controlled, 12-week clinical trial evaluating infliximab as a treatment of bipolar depression. We isolated NEVs using immunoprecipitation against neuronal marker L1CAM from samples collected at baseline and weeks 2, 6 and 12 (endpoint) and measured NEV biomarkers using immunoassays. We assessed neuronal insulin signaling at its first node (IRS-1) and along the canonical (Akt, GSK-3ß, p70S6K) and alternative (ERK1/2, JNK and p38-MAPK) pathways. A subset of participants (n = 27) also underwent whole-brain magnetic resonance imaging (MRI) at baseline and endpoint. Pre-treatment, NEV biomarkers of insulin signaling were independently associated with cognitive function and MRI measures (i.e. hippocampal and ventromedial prefrontal cortex [vmPFC] volumes). In fact, the association between IRS-1 phosphorylation at serine site 312 (pS312-IRS-1), an indicator of insulin resistance, and cognitive dysfunction was mediated by vmPFC volume. In the longitudinal analysis, patients treated with infliximab, a tumor necrosis factor-alpha antagonist with known insulin sensitizing properties, compared to those treated with placebo, had augmented phosphorylation of proteins from the alternative pathway. Infliximab responders had significant increases in phosphorylated JNK levels, relative to infliximab non-responders and placebo responders. In addition, treatment with infliximab resulted in increase in MRI measures of brain volume; treatment-related changes in the dorsolateral prefrontal cortex volume were mediated by changes in biomarkers from the insulin alternative pathway. In conclusion, our findings support the idea that brain insulin signaling is a target for further mechanistic and therapeutic investigations.

Immune response to stress induction as a predictor of cognitive-behavioral therapy outcomes in adolescent mood disorders: A pilot study.

Cognitive-behavioral therapy (CBT) alleviates symptoms of depression in youth with bipolar disorder (BD) and major depressive disorder (MDD). Empirical research has linked inflammatory markers to depressive symptoms and acute psychosocial stress; however, a gap remains as to whether immune response to stress may serve as a putative mechanism of treatment. This preliminary pilot study determined the modest feasibility of assessing psychobiological response to stress as a predictor of CBT outcomes for youth with mood disorders. We evaluated whether participation in a 10-session group-CBT intervention for mood disorders altered inflammatory response to a laboratory psychosocial stress induction and if this alteration in immune stress responsivity was related to a decrease in depressive symptoms. Thirty-four youth (age M = 15.03, SD = 1.91) diagnosed with BD or MDD participated in a 10-session CBT group and pre- and post-group assessments; twenty-eight participants who completed the group had usable cytokine data. Pre- and post-group assessments included stress induction with the Trier Social Stress Test (TSST) during which inflammatory cytokines were measured at baseline (time 0) and after the TSST at 30, 60, and 90 min. Results suggest it is modestly feasible to measure immune response to stress alongside CBT treatment for adolescent mood disorders. Our findings were mixed; across seven cytokines, hierarchical linear models indicated two cytokines, IL6 and IL12, were sensitive to acute laboratory stress. We also found significant correlations between life stress, inflammation, and depression both pre- and post- CBT group. Inflammation pre-group, as measured by IL12 and IL1 ß predicted depressive symptoms following treatment. Although we did not find significant within-subject reductions in inflammation, chronic stress predicted changes in IL ß, signaling the central role of chronic stress. This study offers preliminary evidence that immune responsivity to stress induction could serve as a mechanism of treatment for mood disorders in youth, indicating a potential marker for more personalized model of healthcare.

Personality and pediatric bipolar disorder: Toward personalizing psychosocial intervention.

BACKGROUND: Previous research suggests that challenging temperament characteristics (i.e., low mood, irritability and rigidity) are associated with risk for the development of Pediatric Bipolar Disorder (PBD). This study aimed to investigate the connection between PBD and discrete dimensions of the Five Factor Model (FFM) of personality. METHODS: Youth diagnosed with PBD I, II, or NOS, at high risk for the disorder (BD-HR) and healthy controls were recruited from the Child and Adolescent Psychiatry Outpatient Clinic at Stanford University School of Medicine. Researchers administered a personality inventory and evaluated current mood state. RESULTS: BD and BD-HR youth scored lower in Emotional Regulation than did HC youth (F (3, 70) = 10.75, p < .001). Within the BD and BD-HR groups, youth with high depression scores scored lower on Extraversion (F (3, 70) = 8.62, p < .001) and Conscientiousness (F (3, 70) = 4.53, p < .01). LIMITATIONS: A major limitation of this study is its cross-sectional design, precluding analysis of whether certain traits or clusters of traits predict PBD or other mood disorders. CONCLUSIONS: Low Emotional Regulation, Conscientiousness, and Agreeableness were associated with PBD; this personality profile clinically corresponds with youth diagnosed with PBD who present with difficulty regulating their emotions, vulnerability to stress, and emotional reactivity. Future research examining personality characteristics in PBD may elucidate further a specific profile to aid clinicians in developing psychosocial interventions for youth with and at high risk of developing PBD.

Extracellular Vesicle Biomarkers Reveal Inhibition of Neuroinflammation by Infliximab in Association with Antidepressant Response in Adults with Bipolar Depression.

Accumulating evidence suggests that neuroinflammation is involved in bipolar disorder (BD) pathogenesis. The tumor necrosis factor-alpha (TNF-α) antagonist infliximab was recently reported to improve depressive symptoms in a subpopulation of individuals with BD and history of childhood maltreatment. To explore the mechanistic mediators of infliximab's effects, we investigated its engagement with biomarkers of cellular response to inflammation derived from plasma extracellular vesicles enriched for neuronal origin (NEVs). We hypothesized that infliximab, compared to placebo, would decrease TNF-α receptors (TNFRs) and nuclear factor-kappa B (NF-κB) pathway signaling biomarkers, and that history of childhood abuse would moderate infliximab's effects. We immunocaptured NEVs from plasma samples collected at baseline and at weeks 2, 6, and 12 (endpoint) from 55 participants of this clinical trial and measured NEV biomarkers using immunoassays. A subset of participants (n = 27) also underwent whole-brain magnetic resonance imaging at baseline and endpoint. Childhood physical abuse moderated treatment by time interactions for TNFR1 (χ2 = 9.275, p = 0.026), NF-κB (χ2 = 13.825, p = 0.003), and inhibitor of NF-κB (IκBα) (χ2 = 7.990, p = 0.046), indicating that higher levels of physical abuse were associated with larger biomarker decreases over time. Moreover, the antidepressant response to infliximab was moderated by TNFR1 (χ2 = 7.997, p = 0.046). In infliximab-treated participants, reductions in TNFR1 levels were associated with improvement of depressive symptoms, an effect not detected in the placebo group. Conversely, reductions in TNFR1 levels were associated with increased global cortical thickness in infliximab- (r = -0.581, p = 0.029), but not placebo-treated, patients (r = 0.196, p = 0.501). In conclusion, we report that NEVs revealed that infliximab engaged the TNFR/NF-κB neuro-inflammatory pathway in individuals with BD, in a childhood trauma-dependent manner, which was associated with clinical response and brain structural changes.

Leptin mediates improvements in cognitive function following treatment with infliximab in adults with bipolar depression.

A potential role for leptin in the pathophysiology of bipolar disorder (BD) has been proposed. We recently investigated the effects of the tumor necrosis factor-alpha (TNF-α) antagonist infliximab in individuals with bipolar depression. Leptin is known to interact with the TNF-α system. Herein, we aimed to explore infliximab's effects on leptin and its relationship with brain structure and function. Sixty adults with bipolar depression were enrolled in this randomized, double-blind, 12-week clinical trial of adjunctive infliximab (n = 29) and saline control (n = 31), which were administered intravenously at weeks 0, 2, and 6. Plasma concentrations of leptin, TNF-α and soluble TNF receptors (sTNFR) 1 and 2 were assessed at weeks 0, 2, 6, and 12. We observed a significant decrease in leptin levels in infliximab-treated patients, relative to placebo. Infliximab treatment also significantly reduced TNF-α and sTNFR2, but not sTNFR1 levels. Changes in sTNR2 levels at week 6 significantly determined changes in leptin at week 12 in infliximab-, but not placebo-treated participants. Improvements in verbal memory and increases in global cortical volume were associated with reduction in leptin levels in the treatment group. Mediation analysis indicated that cognitive improvement in infliximab-treated patients was mediated by reductions in leptin levels, which in its turn were determined by decreases in sTNR2 levels. In conclusion, infliximab treatment reduced plasma leptin levels in individuals with BD, through modulation of sTNFR2. Decreases in leptin signaling were associated with an increase in global cortical volume and better performance in a verbal memory task.

Suicidal ideation and depressive symptoms among bipolar patients as predictors of the health and well-being of caregivers.

OBJECTIVES: Few studies have addressed the physical and mental health effects of caring for a family member with bipolar disorder. This study examined whether caregivers' health is associated with changes in suicidal ideation and depressive symptoms among bipolar patients observed over one year. METHODS: Patients (N = 500) participating in the Systematic Treatment Enhancement Program for Bipolar Disorder and their primary caregivers (N = 500, including 188 parental and 182 spousal caregivers) were evaluated for up to one year as part of a naturalistic observational study. Caregivers' perceptions of their own physical health were evaluated using the general health scale from the Medical Outcomes Study 36-item Short-Form Health Survey. Caregivers' depression was evaluated using the Center for Epidemiological Studies of Depression Scale. RESULTS: Caregivers of patients who had increasing suicidal ideation over time reported worsening health over time compared to caregivers of patients whose suicidal ideation decreased or stayed the same. Caregivers of patients who had more suicidal ideation and depressive symptoms reported more depressed mood over a one-year reporting period than caregivers of patients with less suicidal ideation or depression. The pattern of findings was consistent across parent caregivers and spousal caregivers. CONCLUSIONS: Caregivers, rightly concerned about patients becoming suicidal or depressed, may try to care for the patient at the expense of their own health and well-being. Treatments that focus on the health of caregivers must be developed and tested.

Editorial: The Impact of Parental Psychopathology on Family Functioning: Prioritizing Transdiagnostic Interventions With Parents and Families.

Bipolar disorder (BD) in children and adolescents is a severe, refractory illness linked with poor mental and physical health and functional outcomes that confers significant risk over the course of development.1 To date, pharmacotherapy and psychosocial treatment studies have focused largely on symptom reduction and remission as primary outcomes. However, researchers and clinicians who study and treat youth with bipolar spectrum disorders are familiar with a host of functional impairments that often persist even after symptoms have been stabilized.